Sepsis is an all-too-common occurrence in hospitalized patients,
especially in ICUs. These infections originate from a number of
different sources and can be difficult to manage. Many factors must be
taken into account in the treatment of sepsis, including choice of
antibiotic, patient allergies, local sensitivities, origin, site, and
source of infection, and so on. In addition to being difficult to
manage, sepsis contributes significantly to health care burden and has
considerable associated morbidity and mortality concerns.

More than 750,000 cases of sepsis occur each year in the United
States, costing the health care system approximately $17 billion
annually.1,2 It is estimated that between 15% and 35% of hospitalized patients have sepsis.1,2
Sepsis-related infection is one of the most common reasons for ICU
admission and accounts for about 40% of total ICU expenditures.1,3
Furthermore, sepsis is considered one of the leading causes of
noncardiac-related ICU death, with mortality rates approaching 30%.1,3 Proper management is vital to reducing the morbidity, mortality, and costs associated with these infections.

DEFINITIONS

To comprehend sepsis, a basic understanding of several terms is necessary. Bacteremia is simply the presence of bacteria in the blood.4Systemic inflammatory response syndrome
(SIRS) is denoted by two or more of the following clinical symptoms:
(1) body temperature >38°C or <36°C; (2) heart rate >90 beats
per minute; (3) respiratory rate >20 breaths per minute or PaCO2 (partial pressure of carbon dioxide in arterial blood) <32 mmHg; (4) WBC count >12,000 or <4,000 or bands >10%.4Sepsis may be defined as an infection with a positive systemic response (SIRS).5Multiple organ dysfunction syndrome
(MODS) refers to a condition in which homeostasis cannot be maintained
independently in an acutely ill patient with altered organ function.4
Sepsis may be further categorized as severe sepsis or septic shock.
Sepsis occurring in combination with MODS or hypoperfusion is termed severe sepsis.4Septic shock refers to sepsis-induced hypoperfusion despite adequate fluid resuscitation.6

ETIOLOGY AND RISK FACTORS

Male gender and increased age are associated with a greater risk of acquiring sepsis.1,2,7 The rate of infection rises with increasing length of ICU stay and worsening degree of organ failure.3 TABLE 1 lists predictors of mortality in sepsis patients.1-3

Site and Source of Infection

Currently, the most common site of sepsis is the respiratory tract, accounting for 30% to 60% of infections.1-3 The second most common site varies by geographic location.1-3
In the U.S., the bloodstream is the second most common site of
infection, followed by the genitourinary tract and then the abdomen.1 Internationally, the abdomen takes second place, with the bloodstream at 20% and the urinary tract at 14%.2,3 ICU-acquired infections frequently occur in the lungs, are related to catheter access, or involve urinary sites.2

Sepsis acquired in the ICU is more likely to have a mixed microbial etiology.2
Gram-positive and gram-negative bacteria are currently in competition
for the role of most causative pathogen of infection; anaerobic bacteria
and fungi are less commonly implicated.1-3

Gram-Positive Bacteria:Gram-positive bacteria have emerged as the pathogen most commonly associated with sepsis.2,7
This has not always been the case, however. Gram-negative bacteria were
the leading causative organisms until 1987, after which gram-positive
bacteria emerged as the leader. Gram-positive bacteria now account for
nearly 50% of all sepsis cases.2,7 Among these, Staphylococcus species (namely Staphylococcus aureus) are seen most often, with 14% of cultures isolating methicillin-resistant S aureus (MRSA).2,3

Gram-Negative Bacteria:The second most common causative organism in sepsis is typically shown to be gram-negative pathogens.1,2
Interestingly, a 2009 study of ICU infections implicated gram-negative
bacteria as the cause of 62% of all ICU-related infections.3Pseudomonas species and Escherichia coli are the major organisms behind gram-negative–associated sepsis.2,3

Anaerobic Bacteria:Anaerobic bacteria have also been implicated as causative organisms in sepsis infections, but at a rate of only around 4%.2 The most commonly associated anaerobic bacteria are gram-negative bacilli, mainly Bacteroides fragilis.8 Other commonly implicated anaerobes include Peptostreptococcus and Clostridium species.8These
pathogens have been regularly seen in conjunction with other known
causative organisms and intra-abdominal infections (50%-70%).8 A 20% increase in mortality and a 16-day increase in length of hospital stay have been noted with B fragilis infections.8

Fungi: Fungi are causative organisms in about 17% of sepsis cases.2Candida albicans is the most commonly implicated fungus, accounting for 13% of fungal-related sepsis infections.2

SUPPORTIVE THERAPY

The Surviving Sepsis Campaign provides strong recommendations
regarding hemodynamic support and adjunctive therapy in sepsis. See TABLE 2 for current recommendations.

INFECTION MANAGEMENT

Infection management is necessary in order to reduce the morbidity
and mortality associated with sepsis. It is important to remember that
cultures should be obtained prior to initiation of antimicrobial
therapy; however, antibiotics should not be delayed if cultures cannot
be obtained in a timely manner. Antibiotic therapy should be reassessed
daily to ensure that the therapy is appropriate and the patient is
responding adequately with minimal adverse events. Current guidelines
recommend continuation of antibiotics for 7 to 10 days; however, if the
source is found to be noninfectious, antimicrobial therapy should be
promptly discontinued.6

Time to Treatment

Current guidelines recommend that antimicrobial therapy be initiated within 1 hour of identification of septic shock.6
In one retrospective review, when antimicrobial therapy was initiated
within 30 minutes to 1 hour of the onset of hypotension, survival rates
were high (about 80%).9 Survival rates dropped rapidly when antimicrobial treatment was delayed to within the sixth hour (42%).6,9
A recent Cochrane Review, however, found no prospective data to support
the conclusion that early initiation of broad-spectrum antimicrobials
reduces mortality rates in patients with severe sepsis.10 However, prompt initiation of antimicrobial therapy remains important for suspected infections.8,11

Empiric Antimicrobial Therapy

The choice of antimicrobial agent can sometimes be daunting.
Consideration should be given to the origin (i.e., community- or health
care–acquired), site, and source of infection. Recently used antibiotics
should be avoided if possible, and local susceptibilities should be
considered. Broad-spectrum antibiotics are ideal for empiric therapy, as
they provide coverage of multiple organisms. Some suggestions for
empiric management follow. Of course, it is important to use clinical
judgment, factor in local susceptibilities, and consider the patient’s
allergies when initiating empirical antibiotics in any patient.
Furthermore, treatment of the underlying cause may warrant the use of
additional antibiotics.

Monotherapy Versus Combination Therapy: The efficacy of
carbapenem monotherapy has been demonstrated to be equal to the
combination of a beta-lactam plus an aminoglycoside.12 Third-
or fourth-generation cephalosporin monotherapy has been shown to be as
effective as either a beta-lactam or clindamycin plus an aminoglycoside.12
Additionally, in patients with pneumonia, intra-abdominal infections,
or neonatal sepsis, equal efficacy was demonstrated for
extended-spectrum penicillins with or without a beta-lactamase inhibitor
compared with amoxicillin-clavulanate, piperacillin-tazobactam, or
clindamycin in combination with an aminoglycoside.12 Several
of these studies do have limitations, however. Most of the studies
utilized different beta-lactams, involved small sample sizes (<200
patients), and included very few patients with severe sepsis or septic
shock.12 In general, beta-lactam antibiotics have been shown
to be as efficacious as combination therapy with beta-lactams and
aminoglycosides, with fewer renal complications.13 Many experts, however, recommend combination therapy in neutropenic patients and when certain bacteria are suspected, such as Pseudomonas aeruginosa.6,11,14

The take-home point is that monotherapy with broad-spectrum
beta-lactams, while as efficacious as beta-lactams plus an
aminoglycoside, may not be appropriate for all patients.6,11,12,14

MRSA:Empiric coverage of MRSA is important, as higher mortality rates have been associated with inappropriate antibiotic therapy.15,16
Vancomycin is often utilized as empiric therapy for suspected MRSA
infections. It is important to ensure that the minimum inhibitory
concentration is ≤1 mcg/mL upon receipt of cultures.15 If
not, alternative MRSA-susceptible antibiotic therapies (e.g., linezolid,
tigecycline, ceftaroline, or daptomycin) should be considered.

Sites of Infection

Lung:If the site of suspected infection is the
lung, the origin of the infection must be considered. If the infection
is community-acquired, likely pathogens include Streptococcus pneumoniae, Haemophilus influenzae, Legionella species, and Mycoplasma pneumoniae.14
Respiratory fluoroquinolones as monotherapy or a macrolide
antimicrobial, in addition to a beta-lactam (such as a third- or
fourth-generation cephalosporin), are good empiric options for
community-acquired respiratory infections.14 Health care–acquired or –associated infections are often caused by Pseudomonas species, MRSA, Klebsiella species, and anaerobic bacteria.14
These infections can be empirically treated with the combination of a
carbapenem or piperacillin-tazobactam, in addition to levofloxacin or
ciprofloxacin, plus vancomycin.11,14

Urinary Tract:Urinary pathogens include aerobic gram-negative bacilli, such as E coli, Proteus species, Pseudomonas species, and Enterococcus species.14,17
For community-acquired urinary infections, empiric treatment with
ciprofloxacin or levofloxacin is a good choice, as is treatment with
amoxicillin-clavulanate.14 Resistance to fluoroquinolones is
increasing in some regions, so attention should be paid to local
susceptibilities in these instances. For urinary infections that are
health care–acquired or –associated, empiric treatment with
ciprofloxacin or levofloxacin may be considered, as might treatment with
piperacillin-tazobactam or cefepime.14 Pathogens to empirically cover for health care–acquired or –associated infections include Pseudomonas species, MRSA, Klebsiella species, and anaerobes.14
If MRSA is suspected, vancomycin should be added to the empiric
regimen. Treatment with carbapenems is also appropriate; however,
caution should be used in areas with high rates of extended-spectrum
beta-lactamase–producing Enterobacteriaceae.17

Abdomen: Aerobic gram-negative bacilli, anaerobes, and Candida species are commonly associated with intra-abdominal infections.14 These infections may be empirically treated with a carbapenem or piperacillin-tazobactam with or without an aminoglycoside.11,14 Antifungal therapy should be considered.11,14 For suspected B fragilis
or other bacteria that may be resistant to penicillins, the use of a
carbapenem, metronidazole, or a combination penicillin and
beta-lactamase inhibitor should be considered.8,11

Unclear Source:If the source of infection is unknown or difficult to determine, empiric treatment options include carbapenems plus vancomycin.14 These drugs cover a wide array of bacteria, including aerobic gram-negative bacilli, S aureus, and streptococci.14

THE PHARMACIST’S ROLE

Pharmacists are optimally placed to interact with many different
health care professionals, affording them many opportunities to improve
patient care via the optimization of sepsis management. Among these
opportunities are appropriate antibiotic selection, de-escalation of
antibiotic therapy, and sepsis bundle (protocol) implementation.

Selection of Appropriate Antibiotic:As stated
previously, selection of broad-spectrum antibiotics should be targeted
toward likely pathogens. A simple way to accomplish this is to review
the admission diagnosis when entering orders for antibiotics to verify
the indication for antibiotic choice. The pharmacist can also examine
reasons for a change in antimicrobial therapy.

De-escalation of Antibiotic Therapy:Antibiotic
stewardship requires de-escalation of the antibiotic regimen when
necessary. This serves to prevent the unwanted effects of broad-spectrum
antibiotic overuse, such as increased resistance, cost, and adverse
events.18 Once cultures have been obtained and results are
available, antibiotic therapy should be reviewed to ascertain that the
pathogen is susceptible to the prescribed drug regimen. In addition,
consideration should be given to utilizing a more limited spectrum
antibiotic that also shows efficacy.

Sepsis Bundle (Protocol) Implementation:Clinical evidence shows that the treatment of sepsis with evidence-based protocols, or bundles, improves treatment outcomes.19
Sepsis bundles based on the Surviving Sepsis Campaign combine
individual interventions or orders with the goal of improving outcomes.
These bundles place labs and medications on one order form to ensure
that nothing is accidentally omitted. Unfortunately, the implementation
of clinical evidence into practice can present many difficulties,
including provider acceptance, a perception of “cookbook medicine,” and
the approval process.20 As patient advocates, pharmacists are
uniquely positioned to champion acceptance and implementation of such
bundles, as many of the interventions are medication-related. Education
of all involved professionals is key to the buy-in, proper
implementation, and success of sepsis bundles. Of course, outcomes must
be continually assessed to determine the effectiveness of the sepsis
bundle.

CONCLUSION

Sepsis infections, which can be difficult to manage, are common in
hospitalized patients, particularly ICU patients. Proper management is
vital to reducing the morbidity, mortality, and costs associated with
these infections. Since pharmacists are in a position to interact with a
variety of health care professionals, they have the opportunity to
improve patient care through the optimization of sepsis management,
including appropriate antibiotic selection, de-escalation of antibiotic
therapy, and sepsis bundle implementation.

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